Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood behavioral diagnosis. In addition, its symptoms of inattention and impulsivity occur pervasively in many genetic and acquired neurological and psychiatric diseases. Despite the short-term efficacy of psychostimulants to treat core ADHD symptoms in childhood, adult outcomes include high rates of academic underachievement, mental illness, substance abuse, and criminal activity. A critical obstacle to improving long term ADHD treatment outcomes is the lack of quantitative markers which correlate with symptoms and reveal neurobiological mechanisms in ways that could point toward more accurate prognosis and more effective future treatments. In research funded during the initial grant period we addressed this barrier by taking advantage of the relationship (in developmental timing and anatomic proximity) between motor control and both cognitive and emotional control to pursue the physiology of inhibitory mechanisms in ADHD. We developed, refined, and compared techniques to easily and precisely evaluate developing motor function and physiology in 8-12 year old children with ADHD. Using Transcranial Magnetic Stimulation (TMS) in motor cortex, we found that Short Interval Cortical Inhibition (SICI), which is mediated by GABAergic interneurons and modulated by dopaminergic/reward input, is reduced in children with ADHD. Importantly, this SICI reduction correlates with ADHD behavioral symptom severity as well as measures of motor impairment. We also generated novel preliminary findings linking motor cortex GABA, measured with magnetic resonance spectroscopy (MRS), to ADHD and SICI. The broad aim of this application is to 1) develop this ADHD SICI biomarker from resting M1 by extending from baseline (resting) cortical function (rSICI) to informative behavioral (response inhibition) and motivational (reward delay aversion) domains using innovative f(functional)SICI paradigms, 2) clarify the DAergic and GABAergic basis for SICI using pharmacologic challenge and magnetic resonance spectroscopy (MRS) techniques. AIM 1 To quantify fSICI during response inhibition as a biomarker of ADHD. AIM 2 To quantify fSICI during immediate and delayed reward presentation as a biomarker of ADHD. AIM 3 To quantify effects of DA on rSICI and fSICI. AIM 4 To determine whether motor cortex GABA levels 1) differ in ADHD vs. TD and 2) correlate with rSICI and fSICI in Aims 1 and 2. Achieving these aims will lay groundwork for future use of SICI as a pragmatic and biologically meaningful quantitative measure that can be applied to investigations of ADHD treatment, genetics, and risk factors for serious long term outcomes. PUBLIC HEALTH RELEVANCE: Children with Attention Deficit Hyperactivity Disorder (ADHD) experience high rates of academic underachievement, substance abuse, and criminal behavior. Core ADHD impairments in attention, impulse control, and appropriate responses to rewards are difficult to study precisely, which has hindered the development of highly effective treatments. In the first period of this grant, we identified that a quantitative measure in the bran, Transcranial Magnetic Stimulation - evoked Short Interval Cortical Inhibition (SICI), is significantly correlated with ADHD behaviors in 8-12 year old children. The purpose of this study is to measure SICI during impulse control and immediate and delayed reward responses, and to study underlying brain chemical signaling in ways that will direct us to more effective childhood ADHD treatments that prevent adult complications.